EP0718286B1 - Dérivé de 3-alkoxybenzylpiperidine utiles comme agents mélatonergique - Google Patents
Dérivé de 3-alkoxybenzylpiperidine utiles comme agents mélatonergique Download PDFInfo
- Publication number
- EP0718286B1 EP0718286B1 EP95402861A EP95402861A EP0718286B1 EP 0718286 B1 EP0718286 B1 EP 0718286B1 EP 95402861 A EP95402861 A EP 95402861A EP 95402861 A EP95402861 A EP 95402861A EP 0718286 B1 EP0718286 B1 EP 0718286B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- methoxyphenyl
- fluoro
- piperidine
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 208000019116 sleep disease Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- -1 phenylmethyl (benzyl) group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- FZURNOHLERYFRB-UHFFFAOYSA-N cyclopropyl-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]methanone Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(=O)C2CC2)=C1 FZURNOHLERYFRB-UHFFFAOYSA-N 0.000 claims description 4
- 208000017164 Chronobiology disease Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- NWGSYHQHOIZOKC-UHFFFAOYSA-N n-ethyl-4-[(2-fluoro-5-methoxyphenyl)methyl]piperidine-1-carboxamide Chemical compound C1CN(C(=O)NCC)CCC1CC1=CC(OC)=CC=C1F NWGSYHQHOIZOKC-UHFFFAOYSA-N 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- NDTDHXXOWXXCIC-UHFFFAOYSA-N 1-[3-[(3-methoxyphenyl)methyl]piperidin-1-yl]butan-1-one Chemical compound C1N(C(=O)CCC)CCCC1CC1=CC=CC(OC)=C1 NDTDHXXOWXXCIC-UHFFFAOYSA-N 0.000 claims description 2
- WFGLPKQPYHLXHZ-UHFFFAOYSA-N 1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]-2-methylbutan-1-one Chemical compound C1CN(C(=O)C(C)CC)CCC1CC1=CC(OC)=CC=C1F WFGLPKQPYHLXHZ-UHFFFAOYSA-N 0.000 claims description 2
- CERWPTYSEIXGEA-UHFFFAOYSA-N 1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]butan-1-one Chemical compound C1CN(C(=O)CCC)CCC1CC1=CC(OC)=CC=C1F CERWPTYSEIXGEA-UHFFFAOYSA-N 0.000 claims description 2
- ANSXLJPBMPEPQK-UHFFFAOYSA-N 1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]prop-2-en-1-one Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(=O)C=C)=C1 ANSXLJPBMPEPQK-UHFFFAOYSA-N 0.000 claims description 2
- CYCPOEQJKMGQBQ-UHFFFAOYSA-N 1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]propan-1-one Chemical compound C1CN(C(=O)CC)CCC1CC1=CC(OC)=CC=C1F CYCPOEQJKMGQBQ-UHFFFAOYSA-N 0.000 claims description 2
- ZCICWJZHAMAXMQ-UHFFFAOYSA-N 4-[(2-fluoro-5-methoxyphenyl)methyl]-n,n-dimethylpiperidine-1-carboxamide Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(=O)N(C)C)=C1 ZCICWJZHAMAXMQ-UHFFFAOYSA-N 0.000 claims description 2
- LOGUJYRKQQKGOP-UHFFFAOYSA-N 4-[(2-fluoro-5-methoxyphenyl)methyl]-n-methylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NC)CCC1CC1=CC(OC)=CC=C1F LOGUJYRKQQKGOP-UHFFFAOYSA-N 0.000 claims description 2
- IAGGMFXYOXPJTN-UHFFFAOYSA-N 4-[(2-fluoro-5-methoxyphenyl)methyl]-n-propylpiperidine-1-carbothioamide Chemical compound C1CN(C(=S)NCCC)CCC1CC1=CC(OC)=CC=C1F IAGGMFXYOXPJTN-UHFFFAOYSA-N 0.000 claims description 2
- LKAFIOBWCBKUCD-UHFFFAOYSA-N 4-[(2-fluoro-5-methoxyphenyl)methyl]-n-propylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NCCC)CCC1CC1=CC(OC)=CC=C1F LKAFIOBWCBKUCD-UHFFFAOYSA-N 0.000 claims description 2
- MLSGYSAXTBPHMK-UHFFFAOYSA-N 4-[(3-methoxyphenyl)methyl]-n-methylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NC)CCC1CC1=CC=CC(OC)=C1 MLSGYSAXTBPHMK-UHFFFAOYSA-N 0.000 claims description 2
- XDFHCJRKEJALBS-UHFFFAOYSA-N cyclobutyl-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]methanone Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(=O)C2CCC2)=C1 XDFHCJRKEJALBS-UHFFFAOYSA-N 0.000 claims description 2
- GSKZSKFBDZHZSL-UHFFFAOYSA-N cyclopropyl-[4-[(3-methoxyphenyl)methyl]piperidin-1-yl]methanone Chemical compound COC1=CC=CC(CC2CCN(CC2)C(=O)C2CC2)=C1 GSKZSKFBDZHZSL-UHFFFAOYSA-N 0.000 claims description 2
- LSQAOVFONZTKHF-UHFFFAOYSA-N n-ethyl-3-[(3-methoxyphenyl)methyl]piperidine-1-carboxamide Chemical compound C1N(C(=O)NCC)CCCC1CC1=CC=CC(OC)=C1 LSQAOVFONZTKHF-UHFFFAOYSA-N 0.000 claims description 2
- IZDOPBPBLIRBFL-UHFFFAOYSA-N n-ethyl-4-[(3-methoxyphenyl)methyl]piperidine-1-carboxamide Chemical compound C1CN(C(=O)NCC)CCC1CC1=CC=CC(OC)=C1 IZDOPBPBLIRBFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 208000020685 sleep-wake disease Diseases 0.000 claims 2
- LAGNITWTPBPIBN-ONEGZZNKSA-N (e)-1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]but-2-en-1-one Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(=O)\C=C\C)=C1 LAGNITWTPBPIBN-ONEGZZNKSA-N 0.000 claims 1
- XGSLPZRGZZVUJS-UHFFFAOYSA-N 1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]-2-methylpropan-1-one Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(=O)C(C)C)=C1 XGSLPZRGZZVUJS-UHFFFAOYSA-N 0.000 claims 1
- KYDNNAUPCCCRDW-UHFFFAOYSA-N 1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]ethanone Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(C)=O)=C1 KYDNNAUPCCCRDW-UHFFFAOYSA-N 0.000 claims 1
- CLJDESMUQKTRRQ-UHFFFAOYSA-N 1-[4-[(3-methoxyphenyl)methyl]piperidin-1-yl]butan-1-one Chemical compound C1CN(C(=O)CCC)CCC1CC1=CC=CC(OC)=C1 CLJDESMUQKTRRQ-UHFFFAOYSA-N 0.000 claims 1
- JFOIQZYCTOORRC-UHFFFAOYSA-N cyclopentyl-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]methanone Chemical compound COC1=CC=C(F)C(CC2CCN(CC2)C(=O)C2CCCC2)=C1 JFOIQZYCTOORRC-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- CLTYSYWANOLEEM-UHFFFAOYSA-N n-ethyl-2-[(2-fluoro-5-methoxyphenyl)methyl]piperidine-1-carboxamide Chemical compound CCNC(=O)N1CCCCC1CC1=CC(OC)=CC=C1F CLTYSYWANOLEEM-UHFFFAOYSA-N 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 208000035475 disorder Diseases 0.000 abstract description 6
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 abstract description 3
- 208000010412 Glaucoma Diseases 0.000 abstract description 3
- 208000001456 Jet Lag Syndrome Diseases 0.000 abstract description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 3
- 208000026278 immune system disease Diseases 0.000 abstract description 3
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 abstract description 3
- 208000015706 neuroendocrine disease Diseases 0.000 abstract description 3
- 208000011580 syndromic disease Diseases 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 125000000217 alkyl group Chemical group 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 24
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 23
- 229960003987 melatonin Drugs 0.000 description 22
- 239000000203 mixture Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000000034 method Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 102000001419 Melatonin receptor Human genes 0.000 description 6
- 108050009605 Melatonin receptor Proteins 0.000 description 6
- 239000007983 Tris buffer Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IINFVMTZGXTPFP-UHFFFAOYSA-N 4-[(2-fluoro-5-methoxyphenyl)methyl]piperidine Chemical compound COC1=CC=C(F)C(CC2CCNCC2)=C1 IINFVMTZGXTPFP-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000027288 circadian rhythm Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000033458 reproduction Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- HMPVGHXQQIAIAH-UHFFFAOYSA-N (2-fluoro-5-methoxyphenyl)-pyridin-4-ylmethanol Chemical compound COC1=CC=C(F)C(C(O)C=2C=CN=CC=2)=C1 HMPVGHXQQIAIAH-UHFFFAOYSA-N 0.000 description 2
- WVEVTJCZVJYQOS-UHFFFAOYSA-N (3-methoxyphenyl)-pyridin-4-ylmethanone Chemical compound COC1=CC=CC(C(=O)C=2C=CN=CC=2)=C1 WVEVTJCZVJYQOS-UHFFFAOYSA-N 0.000 description 2
- NZVZVGPYTICZBZ-UHFFFAOYSA-N 1-benzylpiperidine Chemical compound C=1C=CC=CC=1CN1CCCCC1 NZVZVGPYTICZBZ-UHFFFAOYSA-N 0.000 description 2
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 2
- PCFUWBOSXMKGIP-UHFFFAOYSA-N 2-benzylpyridine Chemical compound C=1C=CC=NC=1CC1=CC=CC=C1 PCFUWBOSXMKGIP-UHFFFAOYSA-N 0.000 description 2
- JAMXWJXPTWKFNA-UHFFFAOYSA-N 4-[(2-fluoro-5-methoxyphenyl)methyl]pyridine Chemical compound COC1=CC=C(F)C(CC=2C=CN=CC=2)=C1 JAMXWJXPTWKFNA-UHFFFAOYSA-N 0.000 description 2
- VFWKXVIOKYFWIE-UHFFFAOYSA-N 4-[(3-methoxyphenyl)methyl]piperidine Chemical compound COC1=CC=CC(CC2CCNCC2)=C1 VFWKXVIOKYFWIE-UHFFFAOYSA-N 0.000 description 2
- IYGPSEOOQIPIGY-UHFFFAOYSA-N 4-[(3-methoxyphenyl)methyl]pyridine Chemical compound COC1=CC=CC(CC=2C=CN=CC=2)=C1 IYGPSEOOQIPIGY-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 150000001723 carbon free-radicals Chemical class 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000002060 circadian Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 2
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 2
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000033764 rhythmic process Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- WERWVLWJFVIOHK-UHFFFAOYSA-N 1-[4-[(2-fluoro-5-methoxyphenyl)methyl]piperidin-1-yl]-2-methylbutan-1-one;1-[4-[(3-methoxyphenyl)methyl]piperidin-1-yl]butan-1-one Chemical compound C1CN(C(=O)CCC)CCC1CC1=CC=CC(OC)=C1.C1CN(C(=O)C(C)CC)CCC1CC1=CC(OC)=CC=C1F WERWVLWJFVIOHK-UHFFFAOYSA-N 0.000 description 1
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 description 1
- VIPWUFMFHBIKQI-UHFFFAOYSA-N 1-fluoro-4-methoxybenzene Chemical compound COC1=CC=C(F)C=C1 VIPWUFMFHBIKQI-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- AUVALWUPUHHNQV-UHFFFAOYSA-N 2-hydroxy-3-propylbenzoic acid Chemical class CCCC1=CC=CC(C(O)=O)=C1O AUVALWUPUHHNQV-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- YYQAQRNCIJUOLX-UHFFFAOYSA-N 3-[(3-methoxyphenyl)methyl]piperidine;hydrochloride Chemical compound Cl.COC1=CC=CC(CC2CNCCC2)=C1 YYQAQRNCIJUOLX-UHFFFAOYSA-N 0.000 description 1
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- ABGXADJDTPFFSZ-UHFFFAOYSA-N 4-benzylpiperidine Chemical class C=1C=CC=CC=1CC1CCNCC1 ABGXADJDTPFFSZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 0 C*(C)(*)C(CC(*)CCC(*)Cc1cc2ccccc2cc1)=O Chemical compound C*(C)(*)C(CC(*)CCC(*)Cc1cc2ccccc2cc1)=O 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 230000010667 Melatonin Receptor Interactions Effects 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- LUINDDOUWHRIPW-UHFFFAOYSA-N N-[2-(6-chloro-5-methoxy-1H-indol-3-yl)ethyl]acetamide Chemical compound C1=C(Cl)C(OC)=CC2=C1NC=C2CCNC(C)=O LUINDDOUWHRIPW-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000003280 chronobiological effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000007368 endocrine function Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- COJXFXOWPFGTPH-UHFFFAOYSA-N naphthalene;urea Chemical class NC(N)=O.C1=CC=CC2=CC=CC=C21 COJXFXOWPFGTPH-UHFFFAOYSA-N 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 230000001936 parietal effect Effects 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002613 pineal body hormone Substances 0.000 description 1
- 210000004560 pineal gland Anatomy 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004517 retinal physiology Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 210000000221 suprachiasmatic nucleus Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- UAXOELSVPTZZQG-UHFFFAOYSA-N tiglic acid Natural products CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
Definitions
- the invention pertains to novel 3-alkoxybenzylpiperidine derivatives (i.e., amides and ureas of 3- and 4-benzylpiperidines) having drug and bio-affecting properties and to their preparation, pharmaceutical formulations containing them, and use thereof in the manufacture of a medicament for treating certain medical disorders.
- the invention concerns N-acyl 3-benzylpiperidines and N-amido 4-benzylpiperidines having a meta-alkooxy substituent in the phenyl ring of the benzyl moiety. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
- Melatonin ( i ; N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. Melatonin levels show a cyclical, circadian pattern with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms, and the modulation of retinal physiology.
- melatonin agonists should be particularly useful for the treatment of sleep disorders and other chronobiological disorders.
- Melatonin agonists would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, immune disorders, neuroendocrine disorders, and a variety of sleep disorders.
- amide structures Aside from simple indole derivatives of melatonin itself, various amide structures have been prepared and their use as melatonin ligands disclosed. In general these amide structures can be represented as: wherein Z is an aryl or heteroaryl system attached by a two carbon chain to the amide group.
- R is hydrogen or OR 4 wherein R 4 is, inter alia , hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R 1 is hydrogen or COOR 5 wherein R 5 is hydrogen or alkyl; R 2 is hydrogen or alkyl; X is NH or a bond; and R 3 is, inter alia , alkyl, alkenyl, or cycloalkyl.
- R is hydrogen or OR 3 wherein R 3 is, inter alia , hydrogen, lower alkyl, or cycloalkyl; R 1 is hydrogen or lower alkyl; X is oxygen or sulfur; and R 2 is, inter alia , lower alkyl or cycloalkyl.
- arylalkyl(thio)amides 8 as melatonergic ligands, wherein R 1 is hydrogen or lower alkyl; R 2 is hydrogen, halogen, or lower alkyl; R 3 and R 4 are identical or different groups including, inter alia , hydrogen, halogen, or lower alkyl; R 5 is hydrogen or lower alkyl; X is sulfur or oxygen and R 7 is, inter alia , lower alkyl or alkenyl.
- Jacobs et al. in European Patent Application 532177A disclose compounds of type 10 as intermediates in the synthesis of 11 . Neither 9 nor 10 were described as having melatonergic properties.
- the present invention is concerned with compounds of Formula I, which possess melatonergic properties and thus have potential utility in the treatment of conditions affected by melatonin activity.
- R 1 is C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl or NR 7 R 8 where R 7 and R 8 are independently selected from hydrogen and C 1-4 alkyl, but R 7 and R 8 cannot both be hydrogen;
- R 2 , R 3 and R 4 are independently hydrogen or C 1-4 alkyl;
- R 5 is hydrogen, C 1-4 alkyl, halogen or trifluoromethyl;
- R 6 is C 1-4 alkyl;
- X is either oxygen or sulfur; the benzyl group is appended to either the 3- or 4- position of the piperidine ring.
- halogen denotes fluorine, chlorine, bromine and iodine
- C 1-4 alkyl refers to straight and branched chain saturated carbon radicals of from 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, 1-methyl-1-ethyl, 1-methyl-1-propyl, ;
- alkenyl refers to straight and branched carbon radicals of from 2 to 4 carbon atoms containing a carbon-carbon double bond, e.g. ethenyl, propenyl;
- cycloalkyl pertains to homocyclic rings of from 3 to 6 carbon atoms, e.g.
- NR 7 R 8 is meant alkylamino groups wherein R 7 and R 8 are independently selected from H and C 1-4 alkyl, with the proviso that R 7 and R 8 are not both hydrogen.
- the present invention pertains to compounds of Formula I in which R 2 , R 3 and R 4 are hydrogen; R 5 is either hydrogen or 2-fluoro, with the proviso that when R 5 is 2-fluoro the alkoxy group is para to the fluoro group; and R 6 is methyl.
- Preferred compounds of Formula I are those wherein X is O; R 2 , R 3 and R 4 are all H; R 5 is H or 2-fluoro, and R 6 is CH 3 .
- More preferred compounds of the present invention include those in the following list:
- the compounds of Formula I can be prepared as depicted in the following General Scheme.
- the groups R 1 , R 2 , R 3 and X shown in Scheme 1 are as defined hereinabove.
- the additional symbol M appearing in Scheme 1 represents a metal such as magnesium or lithium of a Grignard or organolithium reagent respectively.
- compounds of Formula I also encompass all pharmaceutically acceptable solvates, hydrates being the preferred solvates.
- the present invention also includes stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners of the art.
- the compounds of the present invention have affinity for receptors of the endogenous pineal hormone, melatonin, as determined in a receptor binding assay, and exhibit partial agonist activity as determined by a functional assay; the biological tests are described hereinbelow.
- melatonin is involved in the regulation of a variety of biological rhythms and exerts its biological effects via interaction with specific receptors.
- administration of melatonin agonists are of clinical utility in the treatment of various conditions regulated by melatonin activity. Such conditions include depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, some disorders associated with reproduction, cancer, immune disorders and neuroendocrine disorders.
- the systemic administration and dosing regimen of compounds of Formula I can be considered to be done in a manner similar to that described for melatonin itself.
- the dosage and dosage regimen must be adjusted using sound professional judgment and taking into consideration such variables as the age, body weight, sex and physical condition of the recipient, the route of administration and the nature of the illness being treated.
- Oral, transdermal, subcutaneous, intravenous, intramuscular, rectal, buccal, intranasal, and ocular routes of administrations may be used.
- One or more of the compounds of the invention is mixed with pharmaceutically acceptable amounts of one or more conventional pharmaceutical excipients to produce a formulation to be administered by the desired route.
- such formulations will contain one or several carriers or diluents.
- Useful carriers include solids, semi-solids and liquids which have miscibility, or other compatibility, with the active agent(s) so that they can deliver same to a patient or host.
- Suitable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, mineral oil and the like. Mixtures are operable.
- excipients include lubricants, wetting agents, gellants, emulsifiers, preservatives, colorants, perfumes, flavor enhancers, drying agents and the like. Mixtures can be employed.
- compositions which include the compounds of the invention will contain from about 0.10 to about 10% of active compounds(s) and 99.90 to 90%, or other suitable amounts, of excipient(s).
- Dosage levels will be dictated by the patient's needs and by the medical judgment of the treating physician. Generally, however, dosages of about 0.1 mg to about 100 mg per day are useful to treat sleep or circadian rhythm disorders.
- the compounds of the invention are used in the manufacture of a medicament for treating certain medical disorders.
- one or more dosages of the medicament containing the compound of the invention are administered to an host, preferably a mammalian, e.g. a human host in need of such a medicament.
- NMR nuclear magnetic resonance
- ⁇ parts per million
- TMS tetramethylsilane
- the relative area reported for NMR signals at various chemical shifts corresponds to the number of hydrogen atoms of a particular type in the molecule.
- the multiplicities of the signals are reported as broad singlet (bs), singlet (s), doublet (d), triplet (t), quartet (q) or multiplet (m).
- the NMR spectra were obtained using solutions of the compounds in either deuterodimethylsulfoxide (DMSO-d 6 ) or deuterochloroform (CDCl 3 ).
- Infrared (IR) spectral descriptions include only absorption wave numbers (cm -1 ) having functional group identification value and IR determinations were made using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight. Table 1 lists the IR carbonyl stretching frequencies and elemental analyses of all the specifically claimed compounds of Formula I.
- Butyllithium (47.5 ml of 2.22M solution, 106 mmol) was added slowly to a solution of pentamethyldiethylenetriamine (15 ml) and 4-fluoroanisole (12.61 g, 0.1 mol) in THF (150 ml) at -70°C. The solution was stirred for 2 hr at -75°C and a solution of pyridine-4-carboxaldehyde (9.55 ml, 0.1 mol) in THF was added at -75°C. The mixture was allowed to warm to 25°C slowly and then quenched with ammonium chloride solution. The mixture was diluted with ethyl acetate and the organic layer was separated.
- Process # 1 A specific example of Process # 1 is as follows:
- Process # 3 A specific example of Process # 3 is as follows:
- N-Ethyl-4-[(2-fluoro-5-methoxyphenyl)methyl]-1-piperidinecarboxamide A magnetically stirred solution of 4-[(2-fluoro-5-methoxyphenyl)methyl]-piperidine (0.895 g, 4.01 mmol) in anhydrous dichloromethane (15 mL) at 5 °C was treated dropwise with a solution of ethyl isocyanate (0.320 g, 4.41 mmol) in dry dichloromethane (5 mL). The solution was stirred 0.5 h at 5 °C, allowed to warm to room temperature and stirred for 48 h.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (10)
- Composé de formule I dans laquelleR1 est choisi parmi alkyle inférieur C1-4, alcényle C2-4, cycloalkyle C3-6, et NR7R8 où R7 et R8 sont indépendamment choisis parmi l'hydrogène et un alkyle C1-4 à la condition que R7 et R8 ne soient pas tous les deux hydrogène;R2, R3 et R4 sont indépendamment choisis parmi l'hydrogène et un alkyle C1-4 ;R5 est l'hydrogène, alkyle C1-4, un halogène, ou le trifluorométhyle;R6 est alkyle C1-4 ;X est soit l'oxygène soit du soufre ; et
- Composé selon la revendication 1 choisi dans le groupe comprenant :la 1-Acétyl-4-[(2-Fluoro-5-méthoxyphényl)méthyl]pipéridine ;la 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-1-(2-méthyl-1-oxopropyl) pipéridine :la 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-1-(1-oxobutyl)pipéridine ;la 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-1-(1-oxopropyl)pipéridine ;la 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-1-(1-oxo-2-propényl)pipéridine ;la (E)-4-[(2-Fluoro-5-méthoxyphényl)méthyl]-1-(1-oxo-2-butényl)pipéridine ; etla 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-1-(2-méthyl-1-oxobutyl) pipéridine ;
- Composé selon la revendication 1 choisi dans le groupe comprenant :la 1-(Cyclopropylcarbonyl)-4-[(2-Fluoro-5-méthoxyphényl)méthyl] pipéridine ;la 1-(Cyclobutylcarbonyl)-4-[(2-Fluoro-5-méthoxyphényl)méthyl] pipéridine ; etla 1-(Cyclopentylcarbonyl)-4-[(2-Fluoro-5-méthoxyphényl)méthyl] pipéridine ;
- Composé selon la revendication 1 choisi dans le groupe comprenant :le 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-N,N-diméthyl-1-pipéridinecarboxamide;le 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-N-méthyl-1-pipéridinecarboxamide;le 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-N-propyl-1-pipéridinecarboxamide;le N-Ethyl-4-[(2-Fluoro-1-méthoxyphényl)méthyl]-1-pipéridinecarboxamide ; etl'amide d'acide 4-[(2-Fluoro-5-méthoxyphényl)méthyl]-N-propyl-1-pipéridinecarbothioïque ;
- Composé selon la revendication 1 choisi dans le groupe comprenant :la 1-(Cyclopropylcarbonyl)-4-[(3-méthoxyphényl)méthyl]pipéridine ;la 4-[(3-Méthoxyphényl)méthyl]-1-(1-oxobutyl)pipéridine ;le N-Ethyl-4-[(3-méthoxyphényl)méthyl]-1-pipéridinecarboxamide ;le 4-[(3-méthoxyphényl)méthyl]-N-méthyl-1-pipéridinecarboxamide :la 3-[(3-méthoxyphényl)méthyl]-1-(1-oxobutyl)pipéridine ; etle N-Ethyl-3-[(3-méthoxyphényl)méthyl]-1-pipéridinecarboxamide.
- Composé selon la revendication 1, qui est la :
1-(Cyclopropylcarbonyl)-4-[(2-fluoro-1-méthoxyphényl)méthyl] pipéridine. - Composé selon la revendication 1, qui est la :
1-(Cyclopropylcarbonyl)-4-[(3-méthoxyphényl)méthyl]pipéridine. - Composé selon la revendication 1, qui est le :
N-Ethyl-[(2-Fluoro-5-méthoxyphényl)méthyl]-1-pipéridinecarboxamide. - Composition pharmaceutique pour traiter un trouble du rythme circadien ou du sommeil chez un patient en ayant besoin, comprenant une quantité efficace d'un composé de la revendication 1 et une quantité appropriée d'un véhicule pharmaceutiquement acceptable.
- Utilisation d'une quantité efficace du composé de la revendication 1 dans la fabrication d'un médicament pour traiter un trouble du rythme circadien ou du sommeil chez un patient.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US362337 | 1982-03-26 | ||
US08/362,337 US5530012A (en) | 1994-12-22 | 1994-12-22 | 3-alkoxybenzylpiperidine derivatives as melatonergic agents |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0718286A1 EP0718286A1 (fr) | 1996-06-26 |
EP0718286B1 true EP0718286B1 (fr) | 1998-07-29 |
Family
ID=23425687
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95402861A Expired - Lifetime EP0718286B1 (fr) | 1994-12-22 | 1995-12-18 | Dérivé de 3-alkoxybenzylpiperidine utiles comme agents mélatonergique |
Country Status (9)
Country | Link |
---|---|
US (1) | US5530012A (fr) |
EP (1) | EP0718286B1 (fr) |
JP (1) | JPH08208603A (fr) |
AT (1) | ATE169000T1 (fr) |
AU (1) | AU691057B2 (fr) |
CA (1) | CA2165603A1 (fr) |
DE (1) | DE69503745T2 (fr) |
DK (1) | DK0718286T3 (fr) |
ES (1) | ES2121617T3 (fr) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998010763A1 (fr) * | 1996-09-13 | 1998-03-19 | Merck & Co., Inc. | Inhibiteurs de thrombine |
FR2753706B1 (fr) * | 1996-09-20 | 1998-10-30 | Nouvelles amines cycliques n-substituees, leur procede de preparation et les compositions pharmaceutiques les renfermant | |
AR055916A1 (es) * | 2005-04-22 | 2007-09-12 | Wyeth Corp | Derivados de dihidrobenzofurano, usos de los mismos en la preparacion de un medicamento y composicion farmaceutica |
WO2007117482A2 (fr) * | 2006-04-05 | 2007-10-18 | Vitae Pharmaceuticals, Inc. | Inhibiteurs de la rénine |
WO2007117559A2 (fr) * | 2006-04-05 | 2007-10-18 | Vitae Pharmaceuticals, Inc. | Inhibiteurs de la rénine |
EP2201840B1 (fr) | 2006-09-22 | 2011-11-02 | Pharmacyclics, Inc. | Inhibiteurs de la tyrosine kinase de Bruton |
WO2008124582A1 (fr) * | 2007-04-05 | 2008-10-16 | Smithkline Beecham Corporation | Inhibiteurs de la rénine |
US20100280005A1 (en) * | 2007-04-05 | 2010-11-04 | Baldwin Jonh J | Renin Inhibitors |
MY191929A (en) | 2010-06-03 | 2022-07-18 | Pharmacyclics Llc | The use of inhibitors of bruton's tyrosine kinase (btk) |
EP2877598A1 (fr) | 2012-07-24 | 2015-06-03 | Pharmacyclics, Inc. | Mutations associées à la résistance à des inhibiteurs de la tyrosine kinase de bruton (btk) |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4719219A (en) * | 1982-03-30 | 1988-01-12 | Per A. E. Carlsson | Phenyl-azacycloalkanes and use thereof in treatment of central nervous system disorders |
US5071875A (en) * | 1989-09-25 | 1991-12-10 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
US5151446A (en) * | 1989-09-25 | 1992-09-29 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
FR2658818B1 (fr) * | 1990-02-27 | 1993-12-31 | Adir Cie | Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
FR2674524B1 (fr) * | 1991-03-25 | 1993-05-21 | Adir | Nouveaux amides alkyl heterocycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
FR2680366B1 (fr) | 1991-08-13 | 1995-01-20 | Adir | Nouveaux derives d'arylethylamines, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent. |
GB9216297D0 (en) * | 1991-08-15 | 1992-09-16 | Ici Plc | Therapeutic agents |
FR2680507B1 (fr) | 1991-08-23 | 1993-10-08 | Adir Cie | Nouvelles naphtylethylurees et naphtylethylthiourees, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
FR2689124A1 (fr) | 1992-03-27 | 1993-10-01 | Adir | Nouvelles naphtylalkylamines, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent. |
WO1994000432A1 (fr) * | 1992-06-30 | 1994-01-06 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Derives d'epinephrine anorexiques |
US5449683A (en) * | 1992-10-01 | 1995-09-12 | Massachussetts Institute Of Technology | Methods of inducing sleep using melatonin |
FR2696453B1 (fr) * | 1992-10-02 | 1994-12-23 | Adir | Nouveaux arylalkyl(thio)amides, leur procédé de préparation, et les compositions pharmaceutiques qui les contiennent. |
-
1994
- 1994-12-22 US US08/362,337 patent/US5530012A/en not_active Expired - Fee Related
-
1995
- 1995-12-18 AT AT95402861T patent/ATE169000T1/de not_active IP Right Cessation
- 1995-12-18 DK DK95402861T patent/DK0718286T3/da active
- 1995-12-18 ES ES95402861T patent/ES2121617T3/es not_active Expired - Lifetime
- 1995-12-18 DE DE69503745T patent/DE69503745T2/de not_active Expired - Fee Related
- 1995-12-18 EP EP95402861A patent/EP0718286B1/fr not_active Expired - Lifetime
- 1995-12-19 CA CA002165603A patent/CA2165603A1/fr not_active Abandoned
- 1995-12-21 JP JP7333564A patent/JPH08208603A/ja not_active Abandoned
- 1995-12-21 AU AU40599/95A patent/AU691057B2/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
JPH08208603A (ja) | 1996-08-13 |
EP0718286A1 (fr) | 1996-06-26 |
ATE169000T1 (de) | 1998-08-15 |
DE69503745T2 (de) | 1999-04-29 |
DK0718286T3 (da) | 1999-05-03 |
AU691057B2 (en) | 1998-05-07 |
AU4059995A (en) | 1996-06-27 |
CA2165603A1 (fr) | 1996-06-23 |
ES2121617T3 (es) | 1998-12-01 |
DE69503745D1 (de) | 1998-09-03 |
US5530012A (en) | 1996-06-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1499589B1 (fr) | Derives de n-¬phenyl(piperidin-2-yl)methyl|benzamide, leur preparation et leur application en therapeutique | |
US5661162A (en) | 4-aminomethyl/thiomethyl/sulfonylmethyl-4-phenylpiperdines as tachykinin receptor antagonists | |
US7951821B2 (en) | N-[phenyl(piperidin-2-yl)methyl]benzamide derivatives, preparation thereof, and use thereof in therapy | |
US7790753B2 (en) | Derivatives of N-[phenyl(alkylpiperidine-2-yl)methyl]benzamide, preparation method thereof and application of same in therapeutics | |
US5300507A (en) | New heterocycle-substituted alkylamides | |
KR20120136422A (ko) | 치환된 모르폴린 및 티오모르폴린 유도체 | |
FR2861074A1 (fr) | Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique | |
RU2124012C1 (ru) | Производные индола и содержащие их фармацевтические композиции | |
JP2002530276A (ja) | 新規なピペラジンおよびピペリジン化合物 | |
EP0718286B1 (fr) | Dérivé de 3-alkoxybenzylpiperidine utiles comme agents mélatonergique | |
US6211225B1 (en) | Heterocyclic aminopyrrolidine derivatives as melatonergic agents | |
JP4322675B2 (ja) | ムスカリン受容体アンタゴニストとしてのアミノテトラリン誘導体 | |
WO2004064764A2 (fr) | Peperidines amido alkyle substitues | |
US5252578A (en) | 3-aminochroman compounds | |
US5726188A (en) | Optically active imidazolidinone derivatives and processes for preparing them | |
EA015974B1 (ru) | Производные пирролизина, индолизина и хинолизина, их получение и их применение в терапии | |
US6242448B1 (en) | Trisubstituted-oxazole derivatives as serotonin ligands | |
JPH0552834B2 (fr) | ||
JP2834112B2 (ja) | 新規ムスカリン様レセプターアゴニスト | |
JP2002532472A (ja) | 5−ht1a受容体活性を有するアリールピペリジンおよびアリール−1,2,5,6−テトラヒドロピリジン尿素誘導体 | |
JP2002532471A (ja) | 5−ht1a受容体活性を有するアリールピペリジンおよびアリール−1,2,5,6−テトラヒドロピリジンアミド誘導体 | |
AU705431B2 (en) | Indanylpiperidines as melatonergic agents | |
IL93814A (en) | History of benzothiophyranilamines, their preparation and pharmaceutical preparations containing them | |
JPH08325254A (ja) | 新規なメラトニン作動性インダニルピペラジンまたはホモピペラジン誘導体 | |
JP2001131149A (ja) | 選択的セロトニン再取り込み阻害剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE |
|
17P | Request for examination filed |
Effective date: 19960928 |
|
17Q | First examination report despatched |
Effective date: 19970303 |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE |
|
REF | Corresponds to: |
Ref document number: 169000 Country of ref document: AT Date of ref document: 19980815 Kind code of ref document: T |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REF | Corresponds to: |
Ref document number: 69503745 Country of ref document: DE Date of ref document: 19980903 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
ET | Fr: translation filed | ||
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: BOVARD AG PATENTANWAELTE |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2121617 Country of ref document: ES Kind code of ref document: T3 |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: SC4A Free format text: AVAILABILITY OF NATIONAL TRANSLATION Effective date: 19981021 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed | ||
REG | Reference to a national code |
Ref country code: GB Ref legal event code: IF02 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GR Payment date: 20051111 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: MC Payment date: 20051128 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20051204 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20051206 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20051208 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: AT Payment date: 20051213 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IE Payment date: 20051214 Year of fee payment: 11 Ref country code: GB Payment date: 20051214 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: PT Payment date: 20051215 Year of fee payment: 11 Ref country code: DK Payment date: 20051215 Year of fee payment: 11 Ref country code: DE Payment date: 20051215 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20051228 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20051229 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20060118 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20060220 Year of fee payment: 11 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061218 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061219 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061231 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061231 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061231 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061231 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20061231 Year of fee payment: 12 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070618 |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: MM4A Free format text: LAPSE DUE TO NON-PAYMENT OF FEES Effective date: 20070618 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070701 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070703 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
EUG | Se: european patent has lapsed | ||
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20061218 |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 20070701 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20070831 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061218 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061218 |
|
BERE | Be: lapsed |
Owner name: *BRISTOL-MYERS SQUIBB CY Effective date: 20061231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070102 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20061219 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070102 Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061219 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20061218 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20070704 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20071218 |